Certain terpenoid compounds for insect control

ABSTRACT

Ethers of open chain terpenoid compounds and their monoepoxides were synthesized and found to mimic the juvenile hormones of insects and to be extremely effective as insect control agents.

[ Dec. 23, 1975 Bowers l CERTAIN TERPENOID COMPOUNDS FOR [58] Field ofSearch 424/DIG. 12, 314, 312

INSECT CONTROL [75] Inventor: William S. Bowers, Geneva, N.Y. [56] oTH ggylgi lggfioNs [73] Assignee: The United States of America as represemedby the Secretary of Jardllm, V. et al., Life Sciences, Vol. 8, Part II,pp. Agriculture, Washington, DC. 831-841 (1969) Filed: 25, 1974 PrimaryExaminerV. D. Turner 21 A N 527321 Attorney, Agent, or Firm-M. HowardSilverstein; Max PP O D. Hensley; W. E. Scott Related US. ApplicationData [62] Division of Ser. No. 499,690, Aug. 22, 1974, which is [57]ABSTRACT 3 5 :5 1 9? May 1973' Ethers of open chain terpenoid compoundsand their 191/0 5;; 2 2: dlvlslon of monoepoxides were synthesized andfound to mimic the juvenile hormones of insects and to be extremely 52US. Cl 424/314; 260/484 R; 424/910. 12 effecwe as agents- Int. Cl. A01N9/24 6 Claims, No Drawings CERTAIN TERPENOID COMPOUNDS FOR INSEC CONTROLThis is a division of copending application Ser. No. 499,690, filed Aug.22, 1974, which is a division of Ser. No. 365,295, filed May 23, 1973,now US. Pat. No. 3,852,472, which in turn is a division of Ser. No.78,577, filed Oct. 6, 1970, now abandoned.

This invention relates to insect control and more particularly tocompounds and to the preparation of compounds that have high juvenilehormone activity and which are highly ovicidal to insect eggs.

There is considerable concern throughout the world about the persistenceof many insecticides and insecticide residues in our environment and thepotential hazard that these materials represent to human populations. Inaddition, many species of insect pests have become resistant or immuneto many of the insecticides on the market. Thus, more selectivechemicals are required which will not pose a threat to human populationsand to which the insects will not develop resistance.

The compounds of the present invention should be suitable replacementsfor the insecticides now being used to control stored product insectsand many social pests such as fireants and termites. In addition, it maybe feasible to use these compounds in field applications to control awide variety of insects, the toxicity of the compounds to vertibratesshould be insignificant, and the cost to produce them commerciallyshould be very competitive with that of well known insecticides.

' One object of this invention is to provide a means for achievingselective, safe, economical control of insect pests.

Another object is to provide chemical compounds that prevent insectmaturation when applied topically, when fed to insects or when appliedin a vapor state as a fumigant, to an insect in an immature stage ofgrowth.

A further object of this invention is to provide compounds thatadversely afi'ect the biological function of insects, particularly theirability to mature to an adult stage.

In general, according to the present invention the terpenoid ethers andtheir corresponding epoxides are synthesized and found to prevent insectmaturation when applied to immature stages of several species of insectsby topical application, by feeding or by fumigation (exposure to vapor).Thus an immature insect exposed to these compounds is unable tometamorphose into a normal adult. Topical application of as little as10.0 nanograms (0.0] pg) of the more active compounds in this series issufficient to prevent metamorphosis. The insect which emerges from thetreated pupa retains immature genitalia which preclude copulation andreproduction. The insects die shortly after molting to this adultoidcondition. Also, when used as a vapor or as a dip treatment for eggs thecompounds drastically reduce egg hatch. v

The compounds of this invention'having the following general formula.

wherein Y is R is a straight chain alkyl containing from l-2 carbonatoms such as CH CH CH x is a number from 1 to 2, and

Z is one of the following groups:

.CHCHO(CH2),|CH.1 in which n is O-3;

-CH2CO0(CH2),,CH3 in which n is 0-1;

CH2CH 0H,; and HO-CH2),,CH 5

in which n is 0-3. The terpenoid portions of the compounds were preparedin part by the Marc Julia synthesis [BulL Soc. Chem. France 1072,(1960)] as outlined below.

0 CH CH CH Oxidation was performed with chromic acid solution in acetone[1. Chem. Soc. 2548(l953)] The vinyl alcohols are prepared by thegrignard reaction with vinyl magnesium bromide (or chloride) intetrahydrofuran.

CH R

The vinyl alcohols were converted to the allylic bromides by treatmentwith hydrogen bromide in aqueous or acetic acid solution. Thus, analiquot of the vinyl alcohol was added dropwise to a rapidly stirred icecold aqueous or acetic acid solution containing 2 molar equivalents ofhydrogen bromide. When addition was complete, stirring was continued for20 minutes and then the reaction mixture was poured into an excess ofice cold 5% sodium carbonate solution, extracted with diethyl ether andwashed to neutrality with water. After drying the ethereal extracts oversodium sulfate and removal of the solvent in vacuo, the allylic bromideswere obtained in nearly quantitative yield.

Another series of compounds in which the terpenoid carbon chain was onecarbon longer were prepared in a similar manner except that the bromideswere prepared by a continuation of the Julia synthesis as follows:

Compounds of the general formula Y(CH C=CH(CH ),OA

wherein Y is R is a straight chain alkyl containing from one to twocarbon atoms such as CH CH CH x is a number from 1 to 2; and

A is CH CH O(CH CH or CHZCH la in which n is O to 3;

where synthesized by coupling the foregoing bromides with the respectivealcohols of A to form the corresponding ethers by refluxing the bromidesor stirring at room temperature for several hours with a slight molarexcess of the alcohols and a base such as powdered potassium hydroxideor potassium teritary butoxide in an anhydrous solvent such as diethylether, dimethoxyethane or dimethyl formamide. Alternatively, thereactants were sealed in a small reaction bomb and place in an oven at150C for 2-4 hours.

The reaction mixture was then diluted with water and extracted severaltimes with hexane. The hexane extracts were combined and washed toneutrality with water. The hexane portion was dried over sodium sulfateand the solvent removed in vacuo to yield the crude ethers.

The crude ethers obtained from the foregoing reactions were purified bychromatography over florisil. The

R is a straight chain alkyl containg from 1-2 carbon atoms such as CH CHCH x is a number from 1 to 2; and

E is CH COO(CH ),,CH or 6 in which n is O to l were prepared from theterpenoid The reaction was complete in 1 hour and the reaction alcohols.mixture was extracted with diethyl ether and washed The allylicterpenoid alcohols were prepared from successively with 5% aqueoussodium carbonate and their corresponding vinyl analogs by chromic acidoxiwater. The ethereal extract was dried over anhydrous dation [.l.Chem. Soc. 2548 (1953)] to the conjugated 5 sodium sulfate. The crudeproduct was isolated by aldehyde, followed by reduction to the primaryalcohol evaporation of the solvent in vacuo.

with a metal hydride such as sodium borohydride in The desired compoundswere purified by column methanol, or lithium aluminum hydride in ether.chromatography over florisil as previously described.

CH R CH3 R CRO RC=CH(CH,)2CCH=CH2 RC=CH(CH2)2C=CHCHO CH3 R CH R NaBH,

The primary halides of E, (Br CH COO(CH CH 0r Purity was determined bygas-lipid chromatography and infrared spectroscopy to be greater than99%.

All of the ethers prepared by the foregoing syntheses were thenepoxidized by stirring them in an organic solvent such as benzene,chloroform or methylene Br CHZCHTCHZ chloride during the addition of aslight molar excess of an epoxidizing agent such as m-chloro perbenzoicacid.

were coupled with the terpenoid alcohols under basic Epoxidationoccurred selectively at the terminal douconditions in a reaction bomb,under reflux, or by stirble bond within a few minutes to one hour. Thereacring at room temperature for an extended period of tion mixture waswashed with 5% sodium carbonate time. and then with water to neutrality,and dried over so- CH R CH3 R base dium sulfate. Solvent was removed invacuo.

The epoxides were purified by chromatography over florisil as previouslydescribed.

Purity was ascertained by gas-liquid chromatography and infraredspectroscopy to be greater than 99%.

The compounds and their epoxides prepared by the above procedures areshown in Table l. i Although the general procedures just described arez)2 2).-- 2). 3 undoubtedly adequate for those skilled in the art, thefollowing examples further illustrate the preparation of compoundswithin the scope of each of the general structures shown above.

The crude ethers were purified by chromatography over florisil aspreviously described. Purity was determined by gas-liquid chromatographyand infra-red spectroscopy to be greater than 99%.

Compounds of the general structure wherein Y is Synthesis of Compound 49in Table I o 50 M R Straight chain alkyl containing from 1-2 carbonatoms such as CH CH CH c 06 x is a number from 1 to 2; and H dC, I1 0 Cl/ W I? Y? n is a number from 0 to 3 were prepared by stirring theterpenoid alcohols for 2 hours at room temperature with the appropriatevinyl In a 500 ml. boiling flask, 10.8 g. ethylene glycol ether in thepresence of a catalytic amount of hydrobutyl ether, was combined with10.2 g. potassium tertcmoric id butoxide and 10 g. geranyl bromide in100 ml. dimethoxyethane. The reaction mixture was stirred at roomtemperature for 16 hrs. and then poured into 200 ml. of

H; R 2 l E 0 CH CH C hexane and washed 2X with water and 1X with satu- RC=CH(CH'-)2 CH2OH a rated aqueous sodium chloride solution. The organiccl-i R llayer was dried over anhydrous sodium sulfate and the hexaneremoved in vacuo. 13.6 g. of crude compound was recovered and found tobe suitable for the subse- Epoxidation of Compound 49 in Table l Stirredgm geraniol with 3.5 gm. potassium tert- Dissolved 4 g. of the Compound49 in 50 ml. CH Cl butoxide in 50 ml. dimethoxyethane for 30 minutes.and with stirring added 3.2 g. m-chloroperbenzoic acid Added to above5.8 g. of methyl bromoacetate and in aliquots. Stirred min. and thenmade the solution ti d at room temperature for 16 hrs. Reaction mixbasicwith 10% aqueous Sod um carbdnate- S rippe Off ture dissolved in 200 ml.diethyl ether and washed in a the solvent in vacuo. Residue wasdissolved in diethyl separatory f l ith water 3X. Or a ic layer driedether and Washed in a ep r ry funne With 10% over anhydrous sodiumsulfate. Stripped off solvent in dium carbonate 2X, and water 2X. Driedorganic layer 1 5 vacuQ Yi ld f crude C ound 51 was 7.3 gm. overanhydrous sodium sulfate. Stripped off solvent in Th crude ether was hrt r hed on a column Vacuo- Crude PQ yield was FTaCtiOnatiPH containing150 gm. of florisil. Elution with increasing of the Crude epoxlde Over60 of flonsl] y Stepwlse concentrations of diethyl ether in hexane gavea pure elution with increasing concentrations of diethyl ether f ti t ii 1 4 gm, of Compound 8 l. in hexane gave 3.0 g. pure epoxide. (CompoundNo. 20 57) Synthesis of Compound 65 in Table II on it cm a :0 I ICombined 10 gm. glycerol acetonide and 5.4 gm. Epoxidation of Compound89 in Tablel potassium tert-butoxide in 50 ml. dimethoxyethane andstirred for 20 min. Added 8.2 g. geranyl bromide and continued stirringat room temperature for 16 hrs. I Filtered, stripped offdimethoxyethane, dissolved resi- M c 006/, due in diethyl ether andwashed with water in a separatory funnel 3X. Dried organic layer overanhydrous sodium sulfate and stripped ofi solvent in ether. Crude W H1 Q0 0 (7/3 ether Compound 65 yield was 6.7 gm. o

3 gm. of Compound 65 was fractionated by column chromatography over 70gm. of florisil. Stepwise elution with increasing concentrations ofdiethyl ether in hexane g 19 g of pure Compound 65 Dissolved 1 gm. ofCompound 81 in 25 ml. of

CHCl HeXane (3-2) containing 0.4 gm. sodium bi- Epoxidation of Compound65 in Table II carbonate with stirring in an ice bath. To this was C!!!(b/C43 0 \O f 9 1 c c" M w ichen M Dissolved 1.3 g. of Compound 65 in 30ml. CH CI added dropwise 1.0 gm. m-chloroperbenzoic acid in 25 and addedin aliquots 1.0 gm. of m-Chloroperbenzoic ml. of CHCI Hexane (3-2).After addition, stirring in acid. Reaction stirred 30 min. Solution madebasic with the ice bath was maintained for 15 min. Sodium sulfite 10%aqueous sodium carbonate. Stripped off solvent in was added to destroyany excess peracid. The reaction vacuo. Residue dissolved in diethylether and washed in x ure was diSS0lvd in about 200 ml. of diethyl ethera separatory funnel with 10% sodium carbonate 2X and and Washed in aseparatory funnel with 10% aqueous with water 2X. Dried over anhydroussodium sulfate. Sodium Carbonate 2X and water Organic layer was Crudeepoxide, Compound 73 was 13 dried over anhydrous sodium sulfate and thesolvent The crude epoxide was fractionated by column chropp Offin Vacuo-Yield of Crude Compound 89 was matography as specified for Compound 65.Yield of 126 pure epoxide, Compound 73 was 950 m (Compound The crudeCompound 89 was fractionated over 30 73) gm. of fluorisil as specifiedfor Compound 81 and 770 mg. of pure Compound 89 was obtained. Analysisby synthesls of Compound 81 m Table I gas-chromatography and infrared.(Compound 89) M 4- B CAQCOOCA, AWoc/A Synthesis of Compound 113 in Tablel To a stirred solution of 5 gm. of Compound 145 in Epoxidation ofCompound 1 13 in Table l 100 ml. hexane was added dropwise 4.94 gm.mchloroperbenzoic acid dissolved in- 100 ml. Cl-l Cl After addition,stirring was continued for 20 min. Excess peracid was destroyed withsodium sulfite. The reaction mixture was made basic with 5% aqueouspotassium hydroxide and the solvent stripped off in vacuo. The residuewas dissolved in diethyl ether and washed in a separatory funnel with 5%aqueous potassium hydroxide IX and with water 3X.

Organic layer was dried over anhydrous sodium sulfate and the solventstripped off in vacuo. Yield of crude Compound 153 was 5.0 gm.

Fractionization of 5.0 gm. of Compound 153 by column chromatography over100 gm. of florisil by step- Dissolved 2.24 g. of Compound 113 in 50 ml.Cl-l Cl and with stirring added 2.2 g. m-chloroperbenzoic acid inaliquots. Stirred an additional min., made basic with 10% aqueous sodiumcarbonate, dissolved in 200 ml. diethyl ether and washed with 10%aqueous sodium carbonate 2X and with water 2X in a separatory funnel.

-Organic layer dried over anhydrous sodium sulfate. Yield of crudeCompound 121 was 2.0 gm. Column chromatography of Compound 121 over 60gm. flon'sil by stepwise elution with increasing concentrations ofdiethyl ether in hexane gave 713 mg. of pure Compound 121. Analysis bygas-chromatography and infrared. (Compound 121) Synthesis of Compound145 in Table I wise elution with increasing concentrations of diethylether in hexane gave 3.0 gm. of pure Compound 153. Analysis bygas-chromatography and infrared. (Compound 153).

The morphogenetic effects of some of the compounds in the Tenebriogenitalia assay (Life Sciences 4, 2323-31, 1965) are shown in Table ll.

Topical application to Tenebrio pupae of as little as 10 nanograms (0.01pg) of several compounds (i.e. 25, 26, 28, 57, 73) resultedin theretention of complete pupal genitalia after the ultimate molt toward theadult beetle. Topical application of 100 nanograms (0.1 pg) resulted inthe development of pupal-adult intermediates.

Topical application of somewhat greater amounts of compounds 76, 89,121, 153, were required to induce Geraniol (10 gm.) in 25 ml. diethylether was added dropwise to 14 g. ethyl vinyl ether containing 1 drop ofconcentrated HCl. After addition, stirring was maintained for 2 hrs. ina warm water bath (ca. C.).

The reaction mixture was dissolved in 200 ml. of diethyl ether andwashed in a separatory funnel with 5% aqueous sodium carbonate IX, andwater 3X. The organic layer was dried over anhydrous sodium sulfate. Thesolvent was stripped off "in vacuo. The crude acetal yield was 14.5 gm.

Filtration of 5 gm. of the acetal in hexane through a column containing150 gm. of florisil gave a quantitative return of 5 gm. of pure acetalCompound 145. Purity ascertained by gas-chromatography and infraredanalysis.

Epoxidation of Compound 145 in Table l I MFOCKOCLf/Y 0 retention ofpupal genitalia and/or produce pupal-adult intermediates in Tenebrio. Inall cases the affected insects were unable to form normal adults anddied during or shortly after their ultimate molt without significantfeeding and without any reproduction.

Table Ill shows the effects of compounds 25, 26, 28, 57, 73, 81, 89,153, on the Mexican bean beetle. Topical application of nanogram tomicrogram quantities of these compounds prevents normal adultdevelopment and the insects die during the ultimate molt. Topicaltreatment of Mexican bean beetle eggs with extremely dilute acetonesolutions of these compounds caused severe reduction in egg hatch.

Table IV shows the morphogenetic effects of compounds 25, 26,28, 57, 73,89, 121, 153, on Tenebrio after exposure of the pupae to the vapors ofthese compounds. These results exemplify the potential use of thecompounds as fumigants.

Table 1- Continued Table l- Continued Table 11 Table IV-continuedMorphogenctic Effects of Representative Compounds in the TenebrioGenitalia Assay Compound Micrograms of Compound Required to NumberProduce the Indicated Morphogenctic Effects in PupaLAdult Table lIntermediates Pup-a1 Genitalia 2 Pupal adult intermediates represent anintermediate in which the insect molts to a monster with an essentiallypupal abdomen and an adultoid head and thorax.

' Pupal genitalia refers to the effect in which the insect is nearlyadult but retains immature genitalia.

Each of the above morphogentic effects causes the insect to die shortlythereafter.

Table 111 Reduction in Adult Emergence and Egg Hatch of Mexican BeanBeetle Epilachna varivestis Compound Micrograms of Compound PPM ofCompound Required to cause 90% Required to cause Number in Reduction inadult 90% Reduction in Table I Emergence Egg Hatch 2 'l'opieal treatmentof 2-day old prepupae with an acetone "solution of compound.

" Topical treatment by dipping egg in an acetone solution of compound.

" An acetone control conducted for each of the above treatments showedthat the solvent contributed nothing to the effect of the compounds.

Table IV Morphogentic Effects of Representative Compounds on Tenebriopupae by Fumigation.

Compound Micrograms of Compound Required to Product Pupal-Genitalia andPupal- Number in Adult intermediates by Vapor Expo- Table 1 sureMorphogentic Effects of Representative Compounds on Tenebr o pupae byFumigation.

Micro rams of Compound Re uircd to Pro u et PupaLGenitalia and upal-Adult intermediates by Vapor Expo- Compound Number in Ta e sureCompounds were spread over the lid of a rm diameter petri dish in asmall volume of acetone and after evaporation of the acetone the lid wasplaced over the bottom of the petri dish containing newly meltedTenebrio pupae. The pupae were therefore exposed only to the vapors anddid not come in contact with the compound directly. The insecLs wereleft in the dish until they underwent the final molt toward the adult.

1 claim:

1. A method of controlling the maturation of insects selected from thegroup consisting of Tenebrio molitor (L.) and Epilachna varivestiscomprising contacting said insects at an immature stage of growth withan effective maturation inhibiting amount of a compound of the formula:

5. The method of claim 1 in which the compound is applied as a solute inacetone.

6. A method of preventing the batching of eggs of insects selected fromthe group consisting of Tenebrio molitor (L.) and Epilachna varivestiscomprising applying to said insect eggs an effective egg hatchpreventive amount of a compound of the formula:

where R and R are straight chain alkyls containing from one to twocarbon atoms, x is a number from 1 to 2 and n is a number from 0 to 3.

1. A METHOD OF CONTROLLING THE MATURATION OF INSECTS SELECTED FROM THEGROUP CONSISTING OF TENEBRIO MOLITOR (L) AND EPILACHNA VARIVESTITSCOMPRISING CONTACTING SAID INSECTS AT AN IMMATURE STAGE OF GROWTH WITHAN EFFECTIVE MATURATION INHIBITING AMOUNT OF ACOMPOUND OF THE FORMULA:2. The method of claim 1 in which the compound is applied topically. 3.The method of claim 1 in which the compound is applied as a fumigant. 4.The method of claim 1 in which the compound is fed to the insect.
 5. Themethod of claim 1 in which the compound is applied as a solute inacetone.
 6. A method of preventing the hatching of eggs of insectsselected from the group consisting of Tenebrio molitor (L.) andEpilachna varivestis comprising applying to said insect eggs aneffective egg hatch preventive amount of a compound of the formula: